On One Leg: Trehalose Monoesters Activate Macrophages in a Mincle‐Dependent Manner

Abstract

The C22 and C26 trehalose monoesters, each containing a single acyl chain, were synthesised in good overall yields and found to activate macrophages in a Mincle-dependent manner. The activities of the monoesters paralleled those of their diester counterparts, and both mono- and diesters could activate the immune response in the absence of priming. This is the first time that trehalose monoesters have been found to activate macrophages, and these studies thus provide an important framework for the rational design of other Mincle agonists.

Intracellular metabolite β-glucosylceramide is an endogenous Mincle ligand possessing immunostimulatory activity

“…A common Mincle ligand signature structure has been predicted based on a number of identified ligands (6,7,(33)(34)(35) in combination with the Mincle protein structure (9)(10)(11)(12). A polar head consisting of glucose or mannose and a hydrophobic chain appear to be the minimum requirement for ligand activity.…”

“…As another example, epidermis has a unique GlcCer epidermoside, which is composed of a longer unsaturated ω-hydroxy FA that functions to maintain the epidermal permeability barrier (39,40). Given that glycolipids with longer FA have potent activities (10,11,34,35), epidermosides might be recognized by Mincle on dermal Mϕ/DCs and thereby modulate immune responses in skin. Interestingly, Mincle is involved in the immune response against fungi that causes skin disease (41) through the recognition of its unique glycolipids (7,42).…”

Inflammatory Properties and Adjuvant Potential of Synthetic Glycolipids Homologous to Mycolate Esters of the Cell Wall of <b><i>Mycobacterium tuberculosis</i></b>

“…In future experiments it will be of interest to evaluate such formulations in animal models such as the guinea pigs or human group 1 CD1 transgenic mice [42]. In addition, as already analyzed for TMM [21] and in order to simplify the synthesis process, it would be interesting to determine the minimal carbon chain length necessary for the adjuvant potential of GMM and for its antigenic potential in TB vaccines. More importantly, this study raises an interesting possibility that GMM through Mincle and CD1b may contribute to both innate Results are means ± SD of five mice tested individually and representative of at least four independent experiments.…”

“…For example, recognition of natural arabinose mycolate esters has been described to be dependent on MyD88 and TLR-2 [22], while C-type lectin receptor Mincle and MCL receptor have been associated with recognition of cord factor, its structural analogue TDB, TMM and GMM from corynebacteria [18][19][20][21]34]. In order to identify the signaling pathways involved in the inflammatory responses observed with the synthetic compounds, BMDCs were generated from C57BL/6 WT, Myd88 TNF-α production induced by LPS was dependent on Myd88 but was independent of Myd88 for the synthetic TDM-KB52, TMM-KB51, GMM-SMP73, TDB and natural TDM mix, and also for AraMM-MOD16, in contrast to what was reported for natural AraMM isolated from BCG [22].…”

“…Indeed, it was reported that Mincle (macrophage inducible C-type lectin receptor) does not recognise GMM obtained by trehalase treatment of TDM [18], but that GMM of corynebacteria (C-32 mycolates in corynebacteria versus C-60 to C-90 mycolates in mycobacteria) does bind to Mincle and activates cells [19]. Mincle and MCL (macrophage C-type lectin) have been shown to be essential receptors for recognition of TDM [18,20] and TMM [21] and hence crucial for stimulation of cord factor induced innate immune responses. On the other hand, arabinomycolate ester (a complex mixture of mono-arabinose monomycolates, tetra-arabinose tetramycolates, penta-arabinose tetra-mycolates and hexa-arabinose tetra-mycolates) obtained by acid hydrolysis of BCG cell wall skeleton (CWS) was reported to induce production of TNF-α by mechanisms dependent on TLR-2 / MyD88 pathway [22].…”